INTRODUCTION:

During liver injury, uncontrolled generation of free radicals and proinflammatory genes damages important cells as well as biomolecules, therefore treatment with antioxidant and ant-inflammatory has shown to give protective effects in liver ailments^1-2. Nuclear erythroid 2-related factor 2 (Nrf2) being the key regulator of protective genes which are responsible for inducing anti-inflammatory, cytoprotective and antioxidant effects³. Dysregulation of Nrf2 has been reported as the cause of progression of chronic inflammatory diseases^4-7. In several disease models such as lung injury, sepsis, acute injury of kidney and various liver ailments (such as liver fibrosis, alcoholic liver disease (ALD), non-alcoholic steatohepatitis, non-alcoholic fatty liver disease (NAFLD) and hepatic ischemia-reperfusion injury), Nrf2 pathway has shown its protective effect^8-10.

Activation of Nrf2 modulates the gene expression of the enzymes and proteins responsible for cytoprotection during inflammatory and oxidative stress conditions that ultimately reduces inflammation, reactive oxygen species (ROS) and cell death¹¹. However, Nrf2 is not always protective and is regarded as pleiotropic transcriptional factor and has shown its involvement in resisting cancer treatment and progression of cancer^12-13. The current review describes the beneficial role of Nrf2 in liver ailments and holds recent studies undertaken for evaluation of drugs targeting Nrf2 in liver diseases.

Nrf2 pathway and its role in liver disorders

Nrf2 plays an indispensable role in regulating defensive mechanism against environmental stresses¹⁴. In normal physiological state, most of the Nrf2 gets released into cytosol through its actin-bound inhibitor Kelch-like ECH-associated protein 1 (Keap1) which is a zinc metalloprotein localized close to plasma membrane^14-15. The linkage between Nrf2 and Keap1 gets resolved during oxidative stress and the free Nrf2 heterodimerizes a small Maf (musculoaponeurotic fibrosarcoma) protein after its translocation into nucleus¹⁶. Complex of Nrf2/Maf activate the expression of antioxidant-responsive element (ARE)-reliant gene of proteins responsible for inducing cytoprotective and antioxidative effects. A study has found that fatty acid buildup in liver and oxidative stress was alleviated via Nrf2 activation by increasing the expression of genes implicated in protection and reducing the gene expression for lipogenesis^17-18. One more study revealed that pre-administration of sulforaphane reduced hepatic injury due to I/R (ischemia/reperfusion) by reducing stress due to oxidation by free radicals and sustains normal activities of Na⁺-K⁺-ATPase and Ca²⁺-ATPase; and protection was mediated by Nrf2/ARE signaling pathway¹⁹. Acute liver injury induced due to acetaminophen was reduced as result of p62-Keap1-Nrf2 antioxidant pathway activation¹⁷.

Role of Nrf2 in acute liver injury:

Numerous studies have shown the protective function of Nrf2 in acute liver injury. A study demonstrated that Nrf2 improved acute liver injury induced by cadmium in mice model and showed reduced levels of lactate dehydrogenase (LDH) and alanine transaminase (ALT) with less hepatic hemorrhage as compared to Nrf2-null mice. The defense-associated genes were highly expressed in mice with enhanced Nrf2 that favored protection against oxidative stress. Another study revealed that treatment with mangiferin dose dependently reduced liver injury provoked by lipopolysaccharides (LPS) and d-galactosamine (d-GalN) in mouse models via upregulation of Nrf2 gene expression²⁰. Also, reduced levels of tumor necrosis factor-alpha (TNF-α), aspartate aminotransferase (AST), interleukin-1 beta (IL-1 β) and ALT in serum was observed with the administration of mangiferin. Other natural compounds including oxymatrine, curcumin, biochanin A, madecassoside and morin have also showed protection in animal models of d-GalN and LPS-provoked acute liver injury^20-24. Further, the anti-oxidant Nrf2 pathway was also found protective in models of acute liver injury provoked by acetaminophen and carbon tetrachloride^25-28. Several hepatic ischemia-reperfusion injury (IRI) studies have also identified protective role of Nrf2^29-31. CDDO-Imidazolide, a potent activator of the Nrf2 pathway showed cytoprotective effects in liver IRI by stimulating Nrf2 target gene, heme oxygenase-1 (HO-1) expression and promoted autophagy in hepatocytes that led to reduction in ROS production, mitochondrial DNA and inflammatory responses provoked due to release of damage-associated molecular patterns (DAMP)³¹. Despite of all these evidences, still Nrf2 based treatment for acute liver failure has yet to enter clinical trials.

Role of Nrf2 in ALD:

Alcohol intake has been strictly associated with the growth of liver ailments over decades³². Alcohol metabolism involves oxidation of ethanol by the cytochrome P450 2E1 generates acetaldehyde, giving rise to downstream consequences such as lipid peroxidation, glutathione depletion and ROS generation³³. Besides these, dysregulation of Nrf2 has shown to contribute towards ALD development while upregulation of Nrf2 has shown to improve oxidative stress induced by alcohol through regulation of glutathione metabolism^34-36. Another study demonstrated that upregulation of Nrf2 modulates the expression of very low-density lipoprotein receptor which is responsible for ALD progression. The protective role of Nrf2 as antioxidant was evaluated with the help of Nrf2 inducer D3T in ethanol-exposed mice. D3T treatment considerably reduced ethanol stimulated production of free radicals and apoptosis³⁷. Further it was verified that cytoprotective enzymes generated by Nrf2 upregulation ameliorates alcohol-stimulated liver steatosis. Another drug, sulforaphane which is a Nrf2 activator found in huge amount in vegetables including kale, cabbage and broccoli showed effective results in improving alcohol-stimulated liver steatosis, whereas Nrf2 knock-out mice showed enhanced necroptosis of hepatocytes due to alcohol^38-40. Recently a study confirmed that ethyl pyruvate alleviated ALD in mice as a result of raised expression of peroxisome proliferator-activated receptor (PPAR)-α, mRNA, anti-inflammatory factors and reduced hepatic morphological changes, AST and ALT via upregulation of Nrf2 pathway^{28, 41-42}. On the whole, these indications reveal that activation of Nrf2 displays a defensive role against ALD.

Role of Nrf2 in NAFLD:

The occurrence of NAFLD is constantly growing globally due to fat accumulation in the epithelial cells of liver^43-44. Every third patient suffering from NAFLD may progress towards developing serious non-alcoholic steatohepatitis (NASH)^45-46. Generation of ROS as well as electrophiles is linked to the physiopathology of NASH as demonstrated in ongoing research; hence, initiation of Nrf2 has been regarded as a probable target in the prophylaxis and treatment of NAFLD⁴⁷. Nrf2 stimulation with the use of osteocalcin improved NAFLD by alleviating oxidative stress via inhibiting c-Jun N-terminal kinase (JNK) signaling, which is an essential pathway concerned with physiopathology of NAFLD⁴⁸. Scutellarin, a flavonoid glycoside was reported to improve NAFLD by reducing oxidative stress and considerably lowering blood lipid levels via upregulation of PPAR-γ and its coactivators (1α, Nrf2, HO-1, glutathione S-transferase and nuclear quinone oxidoreductase-1 (NQO-1)) along with the inhibition of nuclear factor κB and Keap1⁴⁹. Furthermore, a stabilizer of PPAR-γ, apigenin by Nrf2-related management of oxidative stress and liver lipid metabolism unveiled to mitigate NAFLD too⁵⁰. Additionally, scutellarin, a natural drug with breviscapine as active constituents showed effective results in preventing NAFLD via improving the Nrf2-mediated antioxidant mechanism in rats fed with high-lipid diet and subjected to chronic stress⁴⁹. Nrf2 displayed protective effects against NASH⁵¹. On the other hand, removal or impairment of Nrf2 has been linked to produce benignant steatosis that may develop into NASH, contributing in worsening of the disease status^52-53. The over stimulation of Nrf2 inhibited the harmful effects brought via deletion of hepatocyte-specific c-met during NASH progression. This study revealed that Nrf2 was able to restore liver damage in mice deficient with hepatocyte-specific c-met by maintaining homeostasis of cellular redox⁵⁴. Ezetimibe and green tea have shown to increase Nrf2 protective effect by opposing fat aggregation and inflammation throughout NASH^55-56.

Synthetic Nrf2 activators:

Existing studies have shown that Nrf2 activation attenuates various liver injuries. Adropin is a secretory signaling peptide involved in dyslipidemia and glucose metabolism. Adropin knocked-out mice were fed either with western diet or methionine-choline deficient diet showed aggravated hepatic steatosis, fibrosis and inflammatory responses, whereas mice treated with adropin showed reduced NASH progression in mice due to increased Nrf2 transcriptional activity and increased glutathione (GSH) levels⁵⁷. 3H-1-2-dithiole-3-thione is an inducer of Nrf2 which enhanced biosynthesis of GSH and detoxified enzymes, such as NQO-1⁵⁸. One of the promising chemo-preventive agents, known as oltipraz is currently under phase III clinical evaluation for NAFLD. Numerous studies have been undertaken for the evaluation of synthetic compounds as Nrf2 activators¹⁷. The calcium channel blocker, verapamil mitigated liver injury in rats induced with thioacetamide toxicity via its anti-inflammatory and antioxidants effects and the mechanism of protection is based on activation of the Nrf2/HO-1 and phosphoinositide-3-kinase-protein kinase (PI3K)/Akt (protein kinase B) pathways⁵⁹. Benazepril have exerted an anti-hepatic fibrosis effect by activating Nrf2 expression or by inhibiting ROS-mediated oxidative stress in response to NADPH oxidase 4 protein (NOX4)⁶⁰. Recently a study showed that dipeptidyl peptidase-4 inhibitor, sitagliptin protected liver from hepatotoxicity by aflatoxin B1 through stimulating Nrf2/ARE/HO-1 pathway⁶¹. A traditional Chinese drug known as Babao Dan (BBD) is known to treat different liver diseases; BBD markedly dispersed acute hepatotoxicity due to ethanol via numerous pathways involving lessening of ethanol-derived oxidative stress via Nrf2 activation and autophagy⁶². Sodium butyrate protected against high-fat diet-induced oxidative stress in rat liver by promoting expression of Nrf2⁶³. Astragaloside IV ameliorated HK-2 cells (immortalized proximal tubule epithelial cell line) apoptosis and oxidative stress induced by high glucose by stimulating Nrf2/ARE signaling pathway⁶⁴. Another study revealed that exendin-4 improved oxidative stress and liver fibrosis in diabetic mice induced by streptozotocin was Nrf2/HO-1 pathway mediated⁶⁵. Sulforaphane showed protective effects in albino Wistar rats induced with hepatotoxicity by arsenic⁶⁶. Sodium butyrate also reduced oxidative stress in rat liver induced with high-fat diet by enhancing the Nrf2 expression⁶³.

Natural compounds as Nrf2 activators:

Recently, Tian et al., (2018) evaluated that acute liver injury induced due to d-GalN/LPS was reduced by phenolic extract obtained from Coreopsis tinctoria via up-regulating PPAR-α, PPAR-γ and Nrf2⁶⁷. Another natural compound ginsenoside Rg1 obtained from ginseng protected liver from injury induced due to acetaminophen via activation of Nrf2 signaling pathway both in vivo and in vitro⁶⁸. Nuciferine, an alkaloid obtained from plants Nymphaea caerulea and N. nucifera has shown to mitigate acute liver injury in mice influenced by alcohol, reduced hepatic inflammation and oxidative stress by altering miR-144/Nrf2/HO-1 cascade⁶⁹. Myristica fragrans kernels (nut mug) also reduced hepatotoxicity brought by paracetamol via activation of anti-apoptotic genes and Nrf2/HO-1 pathway⁷⁰. Gallic acid also reduced necroptosis stimulated due to ethanol via Nrf2-dependent process⁷¹. Polyphenol mixtures obtained from bamboo stems (Phyllostachys nigra variety henosis) also attenuated oxidative stress and liver injury stimulated by phenylhydrazine⁷¹. Another study evaluated that the protective effect exerted by rosmarinic in mice induced with acute liver injury by LPS/d-galN was due to activation of Nrf2/HO-1 signaling pathways and inhibition of the MAPKs/NF-κB signaling pathways^72-75. Another natural product, torularhodin extracted from Sporidiobolus pararoseus has same chemical structure as that of β-carotene. Torularhodin considerably reduced oxidative stress by scavenging free radicals in vitro and reduced d-galactose-induced liver oxidation via stimulating Nrf2/HO-1 pathway in vivo⁷⁶.

CONCLUSION:

So far, there are less pharmacological treatment options for liver diseases. Oxidative stress being one of the pathogenic event in liver injury brings harmful effects, therefore activation of Nrf2 pathway during liver injury exerts antioxidant effect by modulating protective genes, therefore identification of potential Nrf2 activators for treatment of liver ailments is a great challenge, there is an immediate need of potential treatment for liver ailments, therefore both preclinical and clinical evaluation of drugs as Nrf2 activators is needed to discover their therapeutic effect on Nrf2 modulation in the liver disorders.

CONFLICT OF INTEREST:

Authors declare no conflict of interest.

REFERENCES:

1. Muriel P. Role of free radicals in liver diseases. Hepatology International. 2009; 3(4): 526-536.

2. Fauzi NQBA, Vishnupriya V and Gayathri R Fatty liver disease - a review. Research Journal of Pharmacy and Technology. 2016; 9(8): 1263-1267.

3. Vomund S, et al. NRF2, the master regulator of anti-oxidative responses. International Journal of Molecular Sciences. 2017; 18(12): E2772.

4. Chowdhry S, et al. Loss of NRF2 markedly exacerbates nonalcoholic steatohepatitis. Free Radical Biology and Medicine. 2010; 48(2): 357-371.

5. Boutten A, et al. NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease. Trends in Molecular Medicine. 2011; 17(7): 363-371.

6. Sandberg M, et al. NRF2-regulation in brain health and disease: implication of cerebral inflammation. Neuropharmacology. 2014; 79: 298-306

7. Bellezza I. Oxidative stress in age-related macular degeneration: Nrf2 as therapeutic target. Frontiers in Pharmacology. 2018; 9: 1280.

8. Thimmulappa RK, et al. Preclinical evaluation of targeting the NRF2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxidants and Redox Signaling. 2007; 9(11): 1963-1970.

9. Sussan TE, et al. Targeting NRF2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106(1): 250-255.

10. Xu D, et al. The role of NRF2 in liver disease: novel molecular mechanisms and therapeutic approaches. Frontiers in Pharmacology. 2018; 9: 1428.

11. Bataille AM and Manautou JE. NRF2: a potential target for new therapeutics in liver disease. Clinical Pharmacology and Therapeutics. 2012; 92(3): 340-348.

12. Karin M and Dhar D. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis. 2016; 37(6): 541-546.

13. de la Vega MR, Chapman E and Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018; 34(1): 21-43.

14. Kensler TW, Wakabayashi N and Biswal S. Cell survival responses to environmental stresses via the Keap1-NRF2-ARE pathway. Annual Review of Pharmacology and Toxicology. 2007; 47, 89-116.

15. Paupe V, et al. Impaired nuclear NRF2 translocation undermines the oxidative stress response in Friedreich ataxia. PloS One. 2009; 4(1): E4253.

16. Ke B, et al. KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. Journal of Hepatology. 2013; 59(6): 1200-1207.

17. Fan X, et al. Dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways is associated with acetaminophen injury responsive liver regeneration. Drug Metabolism and Disposition. 2014; 42(9): 1532-1539.

18. Lu MC, et al. The Keap1–NRF2–ARE pathway as a potential preventive and therapeutic target: an update. Medicinal Research Reviews. 2016; 36(5): 924-963.

19. Chi X, et al. Sulforaphane reduces apoptosis and oncosis along with protecting liver injury-induced ischemic reperfusion by activating the NRF2/ARE pathway. Hepatology International. 2015; 9(2): 321-329.

20. Liu X, et al. Biochanin A protects lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the NRF2 pathway and inhibiting NLRP3 inflammasome activation. International Immunopharmacology. 2016; 38: 324-331.

21. Pan CW, et al. Andrographolide ameliorates d-galactosamine/lipopolysaccharide induced acute liver injury by activating NRF2 signaling pathway. Oncotarget. 2017; 8: 41202-41210.

22. Xie YL, et al. Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury by activating NRF2 nuclear translocation and inhibiting NF-kB activation. Biomedicine and Pharmacotherapy. 2017; 91: 70-77.

23. Tian Y, et al. Protective effects of morin on lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting TLR4/NF-kappaB and activating NRF2/HO-1 signaling pathways. International Immunopharmacology. 2017; 45: 148-155.

24. Wang W, et al. Madecassoside prevents acute liver failure in LPS/D-GalN-induced mice by inhibiting p38/NFkappaB and activating NRF2/HO-1 signaling. Biomedicine and Pharmacotherapy. 2018; 103: 1137-1145.

25. Huang YJ, et al. Protection against acetaminophen-induced acute liver failure by omentumadipose tissue derived stem cells through the mediation of NRF2 and cytochrome P450 expression. Journal of Biomedical Science. 2016; 23: 5.

26. Cao M, et al. Dibenzoylmethane protects against CCl4-induced acute liver injury by activating NRF2 via JNK, AMPK, and calcium signaling. AAPS Journal. 2017; 19: 1703-1714.

27. Peng X, et al. Curcumin attenuates on carbon tetrachloride-induced acute liver injury in mice via modulation of the NRF2/HO-1 and TGF-beta1/Smad3 pathway. Molecules. 2018; 23: E215.

28. Shen F, et al. Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting NRF2 signaling pathway. Experimental and Therapeutic Medicine. 2018; 15: 4223-4228.

29. Kudoh K, et al. NRF2 activation protects the liver from ischemia/reperfusion injury in mice. Annals of Surgery. 2014; 260: 118-127.

30. Rao J, et al. ATF3-mediated NRF2/HO-1 signaling regulates TLR4 innate immune responsesin mouse liver ischemia/reperfusion injury. Am. J. Transplant 2015; 15: 76-87.

31. Xu D, et al. (2017). The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the NRF2/HO-1 pathway enhanced autophagy. Cell Death and Disease. 2017; 8: E2983.

32. Shepard BD, Tuma DJ and Tuma PL. Chronic ethanol consumption induces global hepatic protein hyperacetylation. Alcoholism: Clinical and Experimental Research. 2010; 34: 280-291.

33. Dey A and Cederbaum AI. Alcohol and oxidative liver injury. Hepatology. 2006; 43: S63-S74.

34. Harvey CJ, et al. NRF2-regulated glutathione Free Radical Biology and Medicine. 2009; 46, 443-453.

35. Lu SC. Glutathione synthesis. Biochimica et Biophysica Acta. 2013; 2013: 3143-3153.

36. Rejitha S, Prathibha P and Indira M. NRF2-mediated antioxidant response by ethanolic extract of Sidacordifolia provides protection against alcohol-induced oxidative stress in liver by upregulation of glutathione metabolism. Redox Report. 2015; 20: 75-80.

37. Dong J, Sulik KK and Chen SY. NRF2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders. Antioxidants and Redox Signaling. 2008; 10: 2023-2033.

38. Song X, et al. Glycycoumarin ameliorates alcohol-induced hepatotoxicity via activation of NRF2 and autophagy. Free Radical Biology and Medicine. 2015; 89: 135-146.

39. Lu C, et al. NRF2 knockdown disrupts the protective effect of curcumin on alcohol-induced hepatocyte necroptosis. Molecular Pharmaceutics. 2016; 13: 4043-4053.

40. Ni YH, Huo LJ and Li TT. Antioxidant axis NRF2-Keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22. World J. Gastroenterology. 2017; 23: 2002-2011.

41. Fawcett TW, et al. Complexes containing activating transcription factor (ATF)/cAMP-responsive element- binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochemical Journal. 1999; 339(Pt 1): 135-141.

42. Harding HP, et al. Perk is essential for translational regulation and cell survival during the unfolded protein response. Molecular Cell 2000; 5: 897-904.

43. Satapathy SK and Sanyal AJ. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin. Liver Disease. 2015; 35: 221-235.

44. Choudhari S and Jothipriya A. Non-Alcoholic Fatty Liver Disease. Research Journal of Pharmacy and Technology. 2016; 9(10): 1782-1785.

45. Tarantino G and Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World Journal of Gastroenterology. 2013; 19: 6735-6743.

46. Dietrich P, and Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Practice and Research Clinical Gastroenterology. 2014; 28: 637-653.

47. Chambel SS, Goncalves AS and Duarte TL. The dual role of NRF2 in nonalcoholic fatty liver disease: regulation of antioxidant defenses and hepatic lipid metabolism. Biomedical Research International. 2015; 2015: 597134.

48. Du J, et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of NRF2and inhibition of JNK. Endocrine. 2016; 53: 701-709.

49. Zhang X., et al. Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARgamma/PGC-1alpha-NRF2 pathway. Free Radical Research. 2018; 52: 198-211.

50. Feng X, et al. Apigenin, a modulator of PPARgamma, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via NRF2 activation. Biochemical Pharmacology. 2017; 136: 136-149.

51. Gupte AA, Lyon CJ and Hsueh WA. Nuclear factor (erythroid derived 2)-like-2 factor (NRF2), a key regulator of the antioxidant response to protect against atherosclerosis and nonalcoholic steatohepatitis. Current Diabetes Reports. 2013; 13: 362-371.

52. Chowdhry S, et al. Loss of NRF2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biology and Medicine. 2010; 48: 357-371.

53. Wang C, et al. NRF2 deletion causes “benign” simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet. Lipids in Health and Disease. 2013; 12: 165.

54. Ramadori P, et al. Genetic NRF2 overactivation inhibits the deleterious effects induced by hepatocyte-specific c-met deletion during the progression of NASH. Oxidative Medicine and Cellular Longevity. 2017; 2017: 3420286.

55. Lee DH, et al. Ezetimibe, an NPC1L1 inhibitor, is a potent NRF2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radical Biology and Medicine. 2016; 99: 520-532.

56. Li J, et al. Green tea extract provides extensive NRF2-independent protection against lipid accumulation and NFkappaB pro- inflammatory responses during nonalcoholic steatohepatitis in mice fed a high-fat diet. Molecular Nutrition and Food Research. 2016; 60: 858-870.

57. Chen X, et al. Adropin protects against liver injury in nonalcoholic steatohepatitis via the NRF2 mediated antioxidant capacity. Redox Biology. 2019; 21: 101068.

58. Kwak MK, et al. Role of transcription factor NRF2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3 H-1, 2-dithiole-3-thione. Molecular Medicine. 2001; 7(2): 135.

59. Mohamed MZ, et al. PI3K/Akt and NRF2/HO-1 pathways involved in the hepatoprotective effect of verapamil against thioacetamide toxicity in rats. Human and Experimental Toxicology. 2019; 38(4): 381-388.

60. Xu YY, Shen FJ and Wu LL. Effect of benazepril on nuclear factor E2 related factor 2, nicotinamide adenine dinucleotide phosphate oxidase and reactive oxygen species in rats with hepatic fibrosis. Chinese Journal of Hepatology. 2019; 27(9): 677-680.

61. Ji Y, et al. Sitagliptin protects liver against aflatoxin B1‐induced hepatotoxicity through upregulating NRF2/ARE/HO‐1 pathway. BioFactors. 2019; [Epub ahead of print].

62. Yu Y, et al. Babao Dan attenuates acute ethanol-induced liver injury via NRF2 activation and autophagy. Cell and Bioscience. 2019; 9(1): 1-12.

63. Sun B, et al. Sodium butyrate protects against high-fat diet-induced oxidative stress in rat liver by promoting expression of nuclear factor E2-related factor 2. British Journal of Nutrition. 2019; 122(4): 400-410.

64. Wang J and Guo H. Astragaloside IV ameliorates high glucose‑induced HK‑2 cell apoptosis and oxidative stress by regulating the NRF2/ARE signaling pathway. Experimental and Therapeutic Medicine. 2019; 17(6): 4409-4416.

65. Fang S, et al. Exendin-4 alleviates oxidative stress and liver fibrosis by activating NRF2/HO-1 in streptozotocin-induced diabetic mice. Journal of Southern Medical University. 2019; 39(4): 464-470

66. Thangapandiyan S, et al. Sulforaphane potentially ameliorates arsenic induced hepatotoxicity in albino Wistar rats: implication of PI3K/Akt/NRF2 signaling pathway. Cellular Physiology and Biochemistry. 2019; 52(5): 1203-1222.

67. Tian Y, et al. Protective effects of Coreopsis tinctoria flowers phenolic extract against D-galactosamine/lipopolysaccharide-induced acute liver injury by up-regulation of NRF2, PPARα, and PPARγ. Food and Chemical Toxicology. 2018; 121: 404-412.

68. Ning C, et al. Ginsenoside Rg1 protects against acetaminophen-induced liver injury via activating NRF2 signaling pathway in vivo and in vitro. Regulatory Toxicology and Pharmacology. 2018; 98: 58-68.

69. Shu G, et al. Nuciferine alleviates acute alcohol-induced liver injury in mice: Roles of suppressing hepatic oxidative stress and inflammation via modulating miR-144/NRF2/HO-1 cascade. Journal of Functional Foods. 2019; 58: 105-113.

70. Dkhil MA, et al. Myristica fragrans kernels prevent paracetamol-induced hepatotoxicity by inducing anti-apoptotic genes and NRF2/HO-1 pathway. International Journal of Molecular Sciences. 2019; 20(4): E993.

71. Zhou Y, et al. Gallic acid protects against ethanol-induced hepatocyte necroptosis via an NRF2-dependent mechanism. Toxicology in Vitro. 2019; 57: 226-232.

72. Yang JH, et al. Bamboo stems (Phyllostachys nigra variety henosis) containing polyphenol mixtures activate NRF2 and attenuate phenylhydrazine-induced oxidative stress and liver injury. Nutrients. 2019; 11(1): 114

73. Li Z, et al. Rosmarinic acid protects mice from lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting MAPKs/NF-κB and activating NRF2/HO-1 signaling pathways. International Immunopharmacology. 2019; 67: 465-472.

74. Affrin JH and Savitha G. Serum gamma glutamyl transferase activity in liver diseases. Research Journal of Pharmacy and Technology. 2018; 11(1): 387-389.

75. Maity T, et al. A review on hepatoprotective herbs for treatment of various liver disorders. Research Journal of Pharmacy and Technology. 2012; 5(5): 602-607.

76. Liu C, et al. Torularhodin Ameliorates Oxidative Activity in Vitro and d-Galactose-Induced Liver Injury via the Nrf2/HO-1 Signaling Pathway in Vivo. Journal of Agricultural and Food Chemistry. 2019; 67(36): 10059-10068.

Received on 04.12.2019 Modified on 11.02.2020

Research J. Pharm. and Tech. 2020; 13(8):3952-3956.

DOI: 10.5958/0974-360X.2020.00699.X